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Substituted purine neuraminidase inhibitors and methods and uses thereof

A compound and drug technology, applied in the field of preventing or treating diseases caused by influenza virus, replacing purine compounds and their pharmaceutical compositions

Active Publication Date: 2016-04-20
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that some virus strains are resistant to Oseltamivir, so there is an urgent need to study new drugs against influenza viruses

Method used

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  • Substituted purine neuraminidase inhibitors and methods and uses thereof
  • Substituted purine neuraminidase inhibitors and methods and uses thereof
  • Substituted purine neuraminidase inhibitors and methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0144] Example 12-amino-9-((3-hydroxycyclobutyl)methyl)-3H-purin-6(9H)-one

[0145]

[0146] Step 1) Methyl 3-oxetanecarboxylate

[0147] Slowly add SOCl dropwise to a solution of 3-oxetanecarboxylic acid (10.0g, 0.088mol) in methanol (50mL) at 0°C 2 (3.1 mL, 0.045 mol), after the addition, the reaction solution was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain the target compound as a colorless oily liquid (10.0 g, >90%).

[0148] MS-ESI:(ESI,pos.ion)m / z:129.2[M+H] + ;

[0149] 1 HNMR (400MHz, CDCl 3 )δ (ppm): 3.77 (s, 3H), 3.23-3.46 (m, 5H).

[0150] Step 2) Methyl 3,3-Dimethoxycyclobutanecarboxylate

[0151] Dissolve methyl 3-oxetanecarboxylate (15g, 117.19mmol) in dichloromethane (50mL), add trimethyl orthoformate (25.7mL, 234.4mmol) and p-toluenesulfonic acid (0.75g, 5 %), the reaction ...

Embodiment 23

[0175] Example 23-(2-Amino-6-oxo-3H-purin-9(6H)-yl)cyclobutanecarboxylic acid methyl ester

[0176]

[0177] Step 1) Methyl 3-Hydroxycyclobutanecarboxylate

[0178] Methyl 3-oxetanecarboxylate (8g, 62.5mmol) was dissolved in THF / MeOH (v / v=1 / 2, 240mL), and sodium borohydride (4.75g, 125mmol) was added at 0°C. Stirring was continued at temperature for 2h. After the reaction, add saturated aqueous ammonium chloride solution (50mL) to the mixture, remove the solvent under reduced pressure to obtain a crude product, add ethyl acetate (150ml) to the crude product to make a slurry and filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (petroleum ether / ethyl acetate (v / v)=3 / 1) gave the target compound (3.2 g, 39%).

[0179] MS-ESI:(ESI,pos.ion)m / z:131.2[M+1] + .

[0180] Step 2) Methyl 3-(methylsulfonyloxy)cyclobutanecarboxylate

[0181] Methyl 3-hydroxycyclobutanecarboxylate (3.2 g, 24.61 mmol) was diss...

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Abstract

The invention provides novel substituted purine compounds or stereoisomers, tautomers, nitric oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof. The substituted purine compounds are used for inhibiting neuraminidase. The invention also provides a drug composition comprising the compounds, and a method for preventing or treating virus infectious diseases by using the compounds or the drug composition.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to substituted purine compounds and pharmaceutical compositions thereof as neuraminidase inhibitors, and the use of the substituted purine compounds and pharmaceutical compositions in preventing or treating diseases caused by influenza viruses. use. Background technique [0002] Influenza, referred to as influenza, is an acute respiratory infectious disease caused by influenza virus. The disease is highly contagious, spread widely, and is often endemic. It is one of the important public health problems to be solved at present. [0003] Two glycoproteins have been found on the surface of influenza virus: hemagglutinin (HA) and neuraminidase (NA). Wherein neuraminidase (NA) is sialidase, and its enzymatic code is EC3.2.1.18, plays the effect of key enzyme (Calfee, D.P.; Hayden, F.G.Drugs, 1998,56 , 537.). NA can catalyze the cleavage of α-glycosidic bonds between sia...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18A61K31/522A61P31/12A61P31/16
CPCC07D473/18
Inventor 任青云刘辛昌罗慧超张健存张英俊
Owner SUNSHINE LAKE PHARM CO LTD